Evidence map›Paper›PMID 38965536›Full record

ArticleJournal of translational medicine2024

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

Kavindra Nath, Pradeep K Gupta, Johnvesly Basappa, Shengchun Wang, Neil Sen, Cosimo Lobello, Jyoti S Tomar, Alexander A Shestov, Stepan Orlovskiy, Fernando Arias-Mendoza and 4 more

Abstract read
In one paragraph

Article in Journal of translational medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Kavindra NathDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA. kavindra.nath@pennmedicine.upenn.edu.
Pradeep K GuptaDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Johnvesly BasappaDepartment of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA.
Shengchun WangDepartment of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA.
Neil SenDepartment of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA.
Cosimo LobelloDepartment of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA.
Jyoti S TomarDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Alexander A ShestovDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Stepan OrlovskiyDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Fernando Arias-MendozaDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Hilka Rauert-WunderlichInstitute of Pathology, University of Würzburg, Würzburg, Germany.
David S NelsonDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Jerry D GlicksonDepartment of Radiology, University of Pennsylvania, 423 Curie Blvd, Philadelphia, PA, 19104-6069, USA.
Mariusz A WasikDepartment of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111-2497, USA. mariusz.wasik@fccc.edu.

Funding

Metabolic Imaging of Targeted Therapies in CancerR01CA268601 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Kavindra Nath, MARIUSZ A. WASIK · 2022 to 2026
$3.0M
Metabolic Biomarkers of Response of Mantle Cell Lymphoma to Bruton Tyrosine Kinase InhibitionR01CA228457 · NCI · UNIVERSITY OF PENNSYLVANIA · PI NATH, KAVINDRA, WASIK, MARIUSZ A. · 2020 to 2024
$2.5M
Melanoma: Metabolic Biomarkers of Response to Targeted TherapyR01CA250102 · NCI · UNIVERSITY OF PENNSYLVANIA · PI BLAIR, IAN ALEXANDER, NATH, KAVINDRA · 2020 to 2024
$2.4M
Translation of Noninvasive Metabolic Biomarkers to Targeted Therapy for CancerR21CA280523 · NCI · UNIVERSITY OF PENNSYLVANIA · PI ARIAS-MENDOZA, FERNANDO, NATH, KAVINDRA · 2024 to 2025
$418k
NCI NIH HHS R21 CA280523NIH HHS R01CA228457NIH HHS R01CA250102NIH HHS R01CA268601NIH HHS R21CA280523
6 · The paper itself

Abstract

backgroundInhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive

methodsWe employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by

resultsEffective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth.

conclusionsOur results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Indexed as

Agammaglobulinaemia Tyrosine KinaseLymphoma, Mantle-CellProtein Kinase InhibitorsAnimalsBiomarkersBiomarkers, TumorCell Line, TumorCell ProliferationHumansMiceSignal TransductionXenograft Model Antitumor AssaysAgammaglobulinaemia Tyrosine KinaseBiomarkersBiomarkers, TumorProtein Kinase InhibitorsACP-196 (acalabrutinib)Bruton’s tyrosine kinase (BTK)Ibrutinib (IBR)Magnetic resonance spectroscopy (MRS)Mantle cell lymphoma (MCL)Proton magnetic resonance spectroscopy (1H MRS)RNA Sequence analysis (RNA-Seq)Signaling inhibitionTricarboxylic or Citric acid cycle (TCA)

Identifiers

PMID38965536
PMCPMC11225145

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